3-179210186-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_006218.4(PIK3CA):c.1252G>A(p.Glu418Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E418E) has been classified as Likely benign.
Frequency
Consequence
NM_006218.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIK3CA | NM_006218.4 | c.1252G>A | p.Glu418Lys | missense_variant, splice_region_variant | 8/21 | ENST00000263967.4 | |
PIK3CA | XM_006713658.5 | c.1252G>A | p.Glu418Lys | missense_variant, splice_region_variant | 8/21 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIK3CA | ENST00000263967.4 | c.1252G>A | p.Glu418Lys | missense_variant, splice_region_variant | 8/21 | 2 | NM_006218.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
PIK3CA related overgrowth syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Washington University in St. Louis | Oct 10, 2023 | The PIK3CA c.1252G>A (p.Glu418Lys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with PIK3CA-related overgrowth spectrum (PROS) disorders (Kuentz P et al., PMID: 28151489; Parker VER et al., PMID: 30270358; Gripp KW et al., PMID: 27191687). This variant has been reported in the ClinVar database as a likely pathogenic variant of somatic origin by one submitter and a variant of uncertain significance by one submitter (ClinVar ID: 45464 ) and has been reported in multiple cancer cases as a somatic variant in the cancer database COSMIC (COSMIC ID: COSV55880477). This variant is absent from the general population (gnomAD v3.1.2), indicating that it is not a common variant. The PIK3CA c.1252G>A (p.Glu418Lys) variant resides within a C2 domain, amino acids 325-484, of PIK3CA that is defined as a critical functional domain (Gymnopoulos M et al., PMID: 17376864). The PIK3CA gene is defined by the ClinGen's Brain Malformations expert panel as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (Lai A et al., PMID: 35997716). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to PIK3CA function. Based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.1252G>A (p.Glu418Lys) variant is classified as pathogenic. - |
PIK3CA-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 31, 2024 | The PIK3CA c.1252G>A variant is predicted to result in the amino acid substitution p.Glu418Lys. This variant has been reported as a mosaic alteration in multiple individuals with PIK3CA-associated overgrowth phenotypes (Gripp et al. 2016. PubMed ID: 27191687; Kuentz et al. 2017. PubMed ID: 28151489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Of note, the p.Glu418Lys variant is located within a kinase domain (p.322-483) critical for p110α protein function, as evaluated by the ClinGen Brain Malformation Variant Curation Expert Panel (Table 3, Lai et al. 2022. PubMed ID: 35997716). Taken together, this variant is interpreted as likely pathogenic. - |
CLOVES syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 19, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at